Int. J. Dev. Biol. 59: 327 - 340 (2015)

https://doi.org/10.1387/ijdb.150197ml

Vol 59, Issue 7-8-9

Special Issue: Ionic Messengers in Development and Cancer

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS

Published: 19 November 2015

Vaibhav P. Pai¹, Joan M. Lemire¹, Ying Chen², Gufa Lin² and Michael Levin*^,1

¹Biology Department, and Center for Regenerative and Developmental Biology Tufts University, Medford, MA, USA and ²Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA

Abstract

Bioelectric signals, particularly transmembrane voltage potentials (V_mem), play an important role in large-scale patterning during embryonic development. Endogenous bioelectric gradients across tissues function as instructive factors during eye, brain, and other morphogenetic processes. An important and still poorly-understood aspect is the control of cell behaviors by the voltage states of distant cell groups. Here, experimental alteration of endogenous V_mem was induced in Xenopus laevis embryos by misexpression of well-characterized ion channel mRNAs, a strategy often used to identify functional roles of V_mem gradients during embryonic development and regeneration. Immunofluorescence analysis (for activated caspase 3 and phosphor-histone H3P) on embryonic sections was used to characterize apoptosis and proliferation. Disrupting local bioelectric signals (within the developing neural tube region) increased caspase 3 and decreased H3P in the brain, resulting in brain mispatterning. Disrupting remote (ventral, non-neural region) bioelectric signals decreased caspase 3 and highly increased H3P within the brain, with normal brain patterning. Disrupting both the local and distant bioelectric signals produced antagonistic effects on caspase 3 and H3P. Thus, two components of bioelectric signals regulate apoptosis-proliferation balance within the developing brain and spinal cord: local (developing neural tube region) and distant (ventral non-neural region). Together, the local and long-range bioelectric signals create a binary control system capable of fine-tuning apoptosis and proliferation with the brain and spinal cord to achieve correct pattern and size control. Our data suggest a roadmap for utilizing bioelectric state as a diagnostic modality and convenient intervention parameter for birth defects and degenerative disease states of the CNS.

Keywords

V_mem, non-cell-autonomous, apoptosis, proliferation, brain, bioelectricity